ABSTRACT

Importance Mental stress can induce myocardial ischemia and also has been implicated in triggering cardiac events. However, pharmacological interventions aimed at reducing mental stress–induced myocardial ischemia (MSIMI) have not been well studied.

Objective To examine the effects of 6 weeks of escitalopram treatment vs placebo on MSIMI and other psychological stress–related biophysiological and emotional parameters.

Interventions Eligible participants were randomized 1:1 to receive escitalopram (dose began at 5 mg/d, with titration to 20 mg/d in 3 weeks) or placebo over 6 weeks.

Main Outcomes and Measures Occurrence of MSIMI, defined as development or worsening of regional wall motion abnormality; left ventricular ejection fraction reduction of 8% or more; and/or horizontal or down-sloping ST-segment depression of 1 mm or more in 2 or more leads, lasting for 3 or more consecutive beats, during 1 or more of 3 mental stressor tasks.

Conclusions and Relevance Among patients with stable coronary heart disease and baseline MSIMI, 6 weeks of escitalopram, compared with placebo, resulted in a lower rate of MSIMI. There was no statistically significant difference in exercise-induced ischemia. Replication of these results in multicenter settings and investigations of other medications for reducing MSIMI are needed.

Figures in this Article

A robust body of evidence has identified emotionalstress as a potential triggering factor in coronary heart disease (CHD) and other cardiovascular events.1- 4 Recognition of the role played by acute emotional stressors in triggering episodes of acute coronary syndromes led to provocation experiments aimed at inducing emotional distress in a controlled setting and documenting reversible impairment of cardiac function. This ultimately resulted in the formal concept of mental stress–induced myocardial ischemia (MSIMI). During the last 3 decades, the association of emotional distress and myocardial ischemic activity in the laboratory has been well studied.5 In the laboratory setting, MSIMI occurs in up to 70% of patients with clinically stable CHD and is associated with increased risk of death and cardiovascular events.5,6

METHODS

The REMIT trial was a randomized, double-blind trial comparing the SSRI escitalopram vs placebo in participants with clinically stable CHD and MSIMI. The study was conducted at the Duke University Health System in the United States. The study protocol was reviewed and approved by the Duke institutional review board, and all participants provided written informed consent.

Eligibility and Recruitment

A complete description of the trial methodology has been published.14 Briefly, we screened all patients with CHD who visited Duke cardiology clinics. Patients 21 years or older were eligible to participate if they had CHD, as documented by angiographic findings of coronary artery stenosis of 70% or greater, history of myocardial infarction, or history of cardiac revascularization. Exclusion criteria included significant cognitive impairment, life-threatening comorbid conditions (estimated 50% mortality within 1 year), active suicidal ideation, and psychiatric conditions precluding use of SSRIs.14 Patients who exhibited MSIMI during baseline screening were qualified for the trial intervention.

Race and ethnicity of the REMIT participants was obtained via self-report using the following investigator-defined categories: Hispanic ethnicity: yes or no; race: white, black, Native American, Asian or Pacific Islander, other (specify).

Overall Design

The REMIT trial tested the hypothesis that the SSRI escitalopram would reduce MSIMI to a greater extent than placebo in patients with clinically stable CHD and MSIMI at enrollment. Participants underwent mental and exercise stress testing during baseline screening. Participants who demonstrated MSIMI were randomly allocated in a 1:1 ratio, divided in blocks of 10, in double-blind fashion to receive escitalopram or matching placebo for 6 weeks. Randomization was conducted by the Duke University Medical Center Investigational Drug Service. All randomization information was secured and accessible only to authorized individuals working within the service.

The initial dose of study drug was 5 mg/d, increasing to 10 mg/d in 1 week and to 20 mg/d at week 3 and for the remainder of the study period. If participants were unable to tolerate higher doses, the dose could be decreased to 5 mg/d. Mental and exercise stress testing were repeated at the end of the 6-week intervention. Adherence to study drug was assessed via weekly inquiries and pill counts on return of medication bottles. Study medication was tapered following end point assessments. Participants who preferred to continue with study medication were provided a prescription for a 1-month supply of escitalopram and required to follow up with their primary cardiologist or primary care physician.

Stress-Induced Myocardial Ischemia

All stress tests were conducted at the Duke Cardiac Diagnostic Unit in the morning, following withholding of β-blockers for 24 to 48 hours.14 Three mental stress tasks—mental arithmetic, mirror trace, and public speaking with anger recall—delivered in the same sequence throughout the study were used to assess MSIMI; each test was followed by a 6-minute rest.

After mental stress testing, participants underwent a treadmill exercise test using the standard Bruce protocol. Exercise testing was terminated according to American College of Sports Medicine guidelines. Testing was repeated at the 6-week end point visit; an alternative mental arithmetic task was used to prevent habituation. Echocardiography and electrocardiography were used to assess ischemia. Left ventricular ejection fraction (LVEF) was calculated from a 3- to 5-beat loop. Wall motion assessments were determined from systole from 1 cardiac cycle at a frame rate of 30 to 40 frames/s using the 16-segment model recommended by the American Society of Echocardiography. These assessments were blinded to randomization and stress tests.

To minimize variation and temporal drift and to enhance reliability, all echocardiographic images from participants who completed both baseline and end point stress testing were batch read by 2 experienced cardiologists (E.J.V., Z.S.) after participants completed the 6-week end point assessments.15 Blood pressure, heart rate, and standard 12-lead electrocardiography were measured simultaneously during acquisition of echocardiographic images. MSIMI was defined by presence of 1 or more ischemic markers: compared with rest measurements, any development or worsening of regional wall motion; reduction of LVEF by 8% or more; and/or deviation of ST segment (horizontal or down-sloping depression of 1 mm or greater) in 2 or more leads, lasting for 3 or more consecutive beats, during 1 or more of the 3 mental stress tasks. Exercise-induced myocardial ischemia (ESIMI) was defined as development of the above during exercise testing. Continuing presence or absence of any of 3 ischemic markers was evaluated at the 6-week end point visit for both MSIMI and ESIMI.

Statistical Analysis

Bivariate analyses by treatment assignment were conducted on demographic and clinical variables. Resting LVEF20 and sex21 have epidemiologic and clinical relevance to the primary outcome and were included in the adjusted model. The primary outcome of presence of MSIMI at 6 weeks and its association with treatment assignment was examined under the intention-to-treat (ITT) principle using logistic regression. We used multiple imputation techniques22 to compensate for potential bias introduced by missing end point data. The imputed model to predict the outcome consisted of age, baseline resting LVEF, sex, and the treatment variable. For our primary outcome, unadjusted and adjusted imputed logistic regression models provided odds ratios (ORs) and 95% CIs for the association of the study intervention with MSIMI. The Hosmer-Lemeshow statistic was reported as a goodness-of-fit index for this model.

For the primary outcome, per-protocol analysis was also conducted among participants who completed baseline and end point assessments. Secondary outcomes were classified into biophysiological and psychological outcomes. A general linear model was used for continuous variables and logistic regression for dichotomized outcomes; these models were controlled for sex and baseline corresponding values. To enhance reliability of mental stress assessments under various domains and reduce the number of statistical tests, we averaged the 3 mental stress measurements. Analysis was also conducted among participants who completed baseline and end point assessments (per-protocol sample) for secondary outcomes. Because the results of the ITT and the per-protocol samples were similar, we chose to present the results of the ITT analyses (Figure). All tests performed were 2-sided.

Primary results were examined at a significance level of .05. For secondary outcomes, α was fixed at .05, and Bonferroni adjustment was used for the number of variables in each domain. This resulted in a critical value of P = .05/9 = .006 for the analysis of the biophysiological outcomes and a critical value of P = .10/7 = .007 for the analysis of the psychological outcomes. All analyses were performed using SAS version 9.3 (SAS Institute Inc).

The study was designed to have at least 80% power to detect between-group differences on MSIMI improvement or no MSIMI at the end of the 6-week treatment period. For a sample of 60 participants in each treatment group, we estimated to observe 30% improvement in MSIMI in the placebo group and greater than 60% MSIMI improvement in the escitalopram group. With these estimates and a 2-sided α = .05, the study had greater than 80% power with up to 10 dropouts. Because we experienced more dropouts than anticipated, with the approval of the study data and safety monitoring board and the Duke institutional review board we increased total enrollment from 120 to 127 to ensure that at least 110 participants completed the baseline and the 6-week assessments.

RESULTS

Participant Characteristics and Baseline Assessments

A total of 127 participants with clinically stable CHD and MSIMI at baseline screening were randomized; 112 (56 in each group) completed end point assessments (Figure). Demographic and clinical characteristics and baseline cardiovascular and emotional measures by treatment group are summarized in Table 1 and Table 2, respectively. Participants allocated to receive escitalopram were significantly older than those assigned to receive placebo (66.5 vs 61.4 years, P = .01). Participants allocated to receive placebo were more likely to be women and had higher rates of resting abnormal wall motion and lower LVEF, although differences between groups were not statistically significant. The majority of participants were taking aspirin, statins, and β-blockers; approximately 45% were taking other antiplatelet agents; and nearly 80% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (Table 1). No differences in medication use by treatment group were noted.

Study Drug Treatment and Discontinuation

Fifteen participants withdrew during the intervention: 8 in the escitalopram group and 7 in the placebo group (Figure). Seven (46.7%) withdrew prior to receiving study medication; 6 (40.0%) withdrew during week 1; and 2 (13.3%) dropped out after week 3. Of these 2 late dropouts, 1 was attributable to the primary cardiologist's request for cardiac catheterization; the other was attributable to death at week 5. Most study participants took the maximum dose of the study drug (54 [87.1%] in the escitalopram group; 57 [93.4%] in the placebo group) (Table 3). Adherence to study medication was defined as taking at least 75% of study medication and was assessed by pill counts at study visits. Overall, 107 of 112 study participants completing end point assessment were considered adherent to study medication (54/56 [96%] in the escitalopram group and 53/56 [95%] in the placebo group).

Primary Outcomes

Of the 127 participants randomized, 64 (50.4%) were allocated to receive escitalopram and 63 (49.6%) to receive placebo. A total of 112 (88.2%; n = 56 for both groups) completed end point assessments (Figure). Although all 127 participants had either new regional wall motion abnormalities, decrease in LVEF of 8% or more, or both during 1 or more of 3 mental stress tests during baseline assessment, 5 of the 112 participants who completed follow-up were reassessed by reviewers (E.J.V., Z.S.) as having no MSIMI at baseline (Table 4). No patients had any mental stress–induced ischemic ST-segment changes, either at baseline or at 6-week assessments. Of 5 participants whose baseline MSIMI was reclassified as “no MSIMI,” 4 had no MSIMI at 6 weeks; 1 participant assigned to receive escitalopram developed MSIMI. Intrarater and interrater variability of wall motion analysis as assessed by the κ statistic ranged from 0.80 to 0.87, consistent with previous results.14

At the end of 6 weeks, more patients taking escitalopram (34.2% [95% CI, 25.4% to 43.0%]) had absence of MSIMI during the 3 mental stressors compared with patients taking placebo (17.5% [95% CI, 10.4% to 24.5%]), based on the unadjusted multiple imputation model for ITT analysis. This analysis showed that the escitalopram group had a significantly higher rate of no MSIMI compared with the placebo group (OR, 2.62 [95% CI, 1.06 to 6.44]; P = .04). The association between escitalopram and MSIMI improvement was no longer statistically significant following adjustment for sex and baseline resting LVEF (OR, 2.53 [95% CI, 0.97 to 6.56]; adjusted P = .06). For the adjusted model, the Hosmer-Lemeshow statistic was 0.56, indicating a good fit. The C index, a measure of predictability, was 0.72. Analysis of the per-protocol population yielded similar results (OR, 2.68 [95% CI, 1.09 to 6.61]; P = .03). The association between escitalopram use and MSIMI improvement remained statistically significant after adjusting for sex and baseline resting LVEF (OR, 2.57 [95% CI, 0.99-6.66]; adjusted P = .05).

Psychological Outcomes

Scores of symptoms of depression, trait anxiety, and perceived stress improved at 6 weeks in both intervention groups, but no differences between groups were observed (Table 5). State anxiety scores improved at week 6 in the escitalopram group and worsened in the placebo group, but the treatment effect was statistically nonsignificant after adjusting for sex and baseline state anxiety (Table 5). Hostility scores remained similar over the 6-week trial across both groups. During end point mental stress testing, participants in the escitalopram group felt significantly more in control and calmer than those in the placebo group. Negative emotional responses to mental stress were less intense in the escitalopram group than in the placebo group, but the group difference was not significant. Participants in the escitalopram group also showed less reduction in positive affect during mental stress; the difference remained significant after adjusting for sex and baseline score (−22.6 [95% CI, −27.4 to −17.9] vs −29.4 [95% CI, −34.2 to −24.6]; P = .05).

Tolerability and Safety

A significantly higher proportion of participants in the escitalopram group reported adverse effects compared with participants in the placebo group (46 [71.9%] vs 28 [44.4%], P = .002) (Table 3). Adverse effects were relatively mild. Two participants withdrew because of adverse effects considered probably attributable to escitalopram (Figure).

DISCUSSION

The REMIT randomized, double-blind, placebo-controlled trial demonstrated that participants with stable CHD receiving escitalopram had an odds of 2.62 of not experiencing MSIMI at week 6, compared with those receiving placebo. Six weeks of escitalopram treatment reduced the number of platelet serotonin receptor transporters and altered the transporter binding affinity density of 5HT uptake sites, compared with the placebo group. Further, the 6-week escitalopram intervention was associated with greater improvements in hemodynamic responses to mental stress and certain measures of psychological functioning, including state anxiety and positive affect, during mental stress. Escitalopram had no effect on exercise-induced ischemia.

MSIMI in patients with clinically stable CHD has been abundantly documented.4,23 Consistent findings demonstrate that MSIMI, as documented by new wall motion abnormality, LVEF reduction of 5% or more or of 8% or more, and/or ischemic changes on electrocardiography, is common in patients with clinically stable CHD.5 MSIMI is not well associated with conventional cardiovascular risks5,23 but like exercise-induced ischemia does predict future adverse cardiovascular prognosis.5,6,24 Some data suggest that MSIMI may offer additional prognostic ability compared with ESIMI.6 However, despite the clinical significance of MSIMI, there has been relatively little investigation of pharmacotherapeutic interventions for this condition. Two previous studies each used a cross-sectional design to test, respectively, the effects of 4 weeks of metoprolol7 on mental stress–induced wall motion abnormality in 19 participants and the effects of 4 weeks of nifedipine GITS (Gastrointestinal Therapeutic System) vs atenolol8 on reduction of mental stress–induced LVEF in 15 patients. Rates of MSIMI prior to study intervention were 74% and 33% in these studies, respectively; because of their small sample sizes, neither study proved definitive.7,8 The present study demonstrates that escitalopram use was associated with an odds ratio of 2.62 for absence of MSIMI compared with placebo. The improvement of MSIMI was seen with both mental stress–induced wall motion abnormality and LVEF decrease of 8% or more (Table 5).

Randomized trials examining cardiovascular benefits of SSRI therapy have yielded mixed results. For instance, both of the SADHART (Sertraline Antidepressant Heart Attack Randomized Trial) studies showed no benefit for sertaline vs placebo for several cardiovascular measurements25 and composite scores.26 However, a secondary analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial found that, after myocardial infarction, depressed patients who received SSRIs during the trial had lower rates of mortality than depressed patients not taking an SSRI.27

Several studies have examined the effects of SSRIs on metabolic risk factors of cardiovascular diseases. A number of investigators have reported that fluoxetine improved insulin sensitivity and glucose tolerance in small samples of patients with type 2 diabetes.28- 33 Kamarck et al34 studied the effects of citalopram on metabolic measurements and hostility in 159 healthy individuals who had high levels of hostility at baseline. The authors reported that 2 months of citalopram (40 mg/d) favorably changed metabolic risk factors, including BMI, waist circumference, glucose levels, levels of high-density lipoprotein cholesterol and triglycerides, insulin sensitivity, and resting diastolic blood pressure (all P < .05 vs placebo). Citalopram also resulted in greater reduction of hostile affect; this reduction was a mediator in the improvement of diastolic blood pressure.11,34 A study by Golding et al10 of 4 weeks of paroxetine therapy in 8 healthy individuals resulted in a 10% to 15% reduction in systolic and diastolic blood pressure responses to mental stress relative to measures obtained while participants were receiving placebo.

Except for weight and BMI, our study did not assess metabolic risk factors. Otherwise, our findings accord with those of Kamarck et al34 and Golding et al.10 The observed lack of significant reductions in weight and BMI and lack of improvement in hostile affect may reflect the shorter duration of the study and the severity of disease among participants. Nonetheless, our findings support the hypothesis that short-term use of SSRIs improves levels of biomarkers associated with adverse cardiovascular prognosis.

Psychosocial functioning (eg, depression, anxiety, and hostility) was not a study selection criterion. We deliberately did not specify the potential psychological effects of escitalopram on participants during consent and intervention, because the study primarily aimed at assessing effects on MSIMI. Similar to Kamarck et al,34 we did not find that escitalopram had a favorable effect on reducing depressive symptoms. Although state anxiety improved among participants receiving escitalopram, especially with regard to emotional reactions to mental stress testing, trait anxiety remained unchanged. This might be attributable to the short-term intervention, might reflect a study population without clinically significant depression and anxiety, or both. However, participants receiving escitalopram reported feeling calmer and more in control during the week 6 mental stress protocol relative to those receiving placebo. This finding is notable because positive expectations and attitudes have been shown to be associated with lower rates of mortality in patients with CHD.35

Myocardial ischemia reflects an imbalance in a complex process involving increases in the determinants of myocardial oxygen demand as well as decrease of coronary blood supply.36 Hemodynamic responses to mental stress differ fundamentally from exercise-induced stress, in that mental stress causes little increase in heart rate and a lower-grade increase in systolic blood pressure relative to physical stress.23 The underlying pathological process of MSIMI is poorly understood. Current models posit that MSIMI is attributable to constriction of small or microcoronary arteries in the context of endothelial dysfunction or atherosclerosis, resulting from dysregulation of the central nervous system and hypothalamic-pituitary-adrenal axis system in response to emotional stress. Our study shows that escitalopram can significantly reduce MSIMI that cannot be modified by conventional anti-ischemic agents and suggests that enhancing central synaptic availability of serotonin may be an important step in management of CHD.

Another potential mechanistic explanation is that SSRIs reduce platelet aggregation.37 Reduction of platelet aggregation through inhibition of the 5HT receptor by the receptor agonist, even when initiated after onset of recurrent thrombosis, significantly improved coronary patency in a canine model.38 Escitalopram was seen to significantly alter platelet serotonin receptor transport volume and affinity in our study. Further evaluation of associations of such alterations with changes in platelet aggregation and MSIMI will provide additional mechanistic insight. Whether MSIMI improvement results from changes in cardiovascular reaction to mental stress, psychological modification, or both deserves further exploration.

Limitations

A number of limitations of our study should be noted. Prestratification of baseline demographic and clinical characteristics for equal randomization was not applied because of the relatively small sample size. In addition, based on the multiple-imputation ITT analysis, rates of MSIMI in the treatment group (65.8%) and the placebo group (82.5%) were higher than the original estimate (40% and 70% in treatment and placebo groups, respectively). The study power was thus lower than expected.14 In addition, although dropout of participants was balanced between treatment groups, the number of dropouts could potentially have had an effect on our findings.

The present study did not address whether reductions in MSIMI at 6 weeks reached the ceiling effect and was not designed to test SSRI effects on major adverse cardiovascular events. In addition, we delivered the 3 mental tasks in the same sequence throughout the study for comparative consistency; thus, individual task potency could not be evaluated. Further, it is possible that an effect on MSIMI caused by 1 task might have been carried forward to affect a subsequent task, although we believe the 6-minute rest period would allow the cardiovascular system to recover from the stress. However, because the primary outcome assessed whether a participant had MSIMI with any of the 3 mental tasks, study findings were not adversely affected by such an arrangement. The REMIT trial was conducted at a single large tertiary-care academic medical center; as such, study findings may not be generalizable to different patient populations or care environments. In addition, the limited power leaves uncertainty about the precise magnitude of the effects of treatment. The loss of statistical significance after adjustment for sex and baseline LVEF adds ambiguity to the interpretation of the findings and emphasizes the need for confirmation of these results in other trials before they are considered definitive.

In summary, 6-week pharmacologic enhancement of serotonergic function superimposed on the best evidence–based management of CHD appeared to significantly improve MSIMI occurrence. These results support and extend previous findings suggesting that modifying central and peripheral serotonergic function could improve CHD symptoms and may have implications for understanding the pathways by which negative emotions affect cardiovascular prognosis.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. All authors reported receiving salary support through a National Heart, Lung, and Blood Institute (NHLBI) research grant. Dr Jiang reported that she is named on a patent application to Duke University related to selective serotonin reuptake inhibitor (SSRI) treatment for mental stress–induced myocardial ischemia (MSIMI). Dr Velazquez reported receiving research grants from Abbott Laboratories, Evalve, and Ikaria; receiving consulting fees from Boehringer Ingelheim, Gilead, and Novartis; and that he is named on a patent application to Duke University related to SSRI treatment for MSIMI. Dr Samad reported receiving a grant or grant pending from the American Society of Echocardiography. Dr Becker reported receiving research grant support from Baxter, Bristol-Myers Squibb, Johnson & Johnson, and Regado Biosciences; receiving consulting/lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Regado Biosciences, and sanofi-aventis. Dr Ortel reported serving as a consultant for Instrumentation Laboratory, Boehringer Ingelheim, and Bayer and receiving grants or grants pending from GlaxoSmithKline, Eisai, Pfizer, Daiichi Sankyo, Instrumentation Laboratory, and Stago. Dr Williams reported holding a US patent on the 5HTTLPR L allele for use as a marker of increased cardiovascular risk in stressed persons and that he is a founder and major stockholder of Williams LifeSkills Inc. Dr Rogers reported receiving funding from Boston Scientific Corporation, HeartWare, and Thoratec Corporation. Dr O’Connor reported receiving funding from Actelion Pharmaceuticals Ltd, Amgen Inc, Biscardia LLC, Faculty Connection, GE Healthcare, Ikaria, Novella Clinical Inc, Pfizer Inc, Pozen, and Roche Diagnostics; serving as a consultant for Novartis, Heartware, ResMed, Johnson & Johnson, Gilead, Critical Diagnostics, BG Medicine, Otsuka, Astellas, Cytokinetics, and Capricor; holding stock or stock options in Neurotronik/Interventional Autonomics Corporation; that he is named on a patent application to Duke University related to SSRI treatment for MSIMI; and serving as a journal editor for the American College of Cardiology. No other authors reported disclosures.

Funding/Support: The REMIT study was funded by the NHLBI (R01 HL085704), Bethesda, Maryland. Escitalopram and matched placebo were supplied by Forest Research Institute Inc, Germantown, Maryland.

Role of the Sponsor: The sponsors of this study had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Additional Contributions: We would like to thank Kirkwood Adams, MD (Department of Medicine, University of North Carolina–Chapel Hill School of Medicine), Alan Miller, MD (Department of Medicine, University of Florida College of Medicine–Jacksonville), and Zhen Huang, MS (Duke Clinical Research Institute–Statistics, Durham, North Carolina), for their contributions as the data and safety monitoring board of the REMIT study. These persons received no compensation from REMIT trial funding sources for their contributions. We would like also to thank Jonathan McCall, MS, for his editorial assistance. Mr McCall, an employee of the Duke Clinical Research Institute, received no compensation for his work on this manuscript other than his usual salary.

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